Abstract LB-092: Induction of IL-17-mediated cellular immunity targeting MUC1 through vaccination

Abstract

Abstract Prophylactic vaccination targeting tumor-associated antigens (TAA) holds the potential to prevent the development of cancer. Clinical evidence has demonstrated a protective effect of cellular immunity against the mucin 1 (MUC1) TAA, expressed by ∼90% of mammary tumors. Nevertheless, conventional vaccination strategies have failed to prevent breast cancer due to the induction of terminally differentiated, short-lived Th1 cells of limited functionality. By contrast, IL-17-producing T cells, including CD4+ Th17 and CD8+ Tc17 subtypes, account for pathogenic agents that escape Th1-mediated control and are thus endowed with specialized, non-redundant mechanisms to promote inflammation at the cell and tissue levels. Recent studies have confirmed that signaling through the inducible T-cell co-stimulator (ICOS) pathway is sufficient to polarize T cells towards IL-17-expression in vitro, providing a novel mechanism to induce Th17/Tc17-mediated immunity against tumors in vivo. To generate IL-17-mediated antitumor immunity through vaccination, we examined the immunogenicity of combinations of adenoviral vectors encoding MUC1, ICOS ligand (ICOS-L) and the cytokines IL-6 and IL-23, implicated in Th17 development and expansion, respectively. Vaccination against MUC1, in the presence or absence of IL-17-polarizing conditions, overcame immune tolerance in transgenic mice recognizing MUC1 as a “self” antigen, inducing robust MUC1-specific intracellular IFNγ production from CD8+ T cells detected by FACS. Co-administration of vectors encoding MUC1 and ICOS-L, with or without vector-derived IL-6 and/or IL-23, induced significant IL-17 production in response to mitogen from both CD4+ and CD8+ T cells compared to MUC1 vaccination alone. Interestingly, ICOS-L augmentation resulted in the upregulation of the master Th17 transcription factor RORγt in CD4+, but not CD8+ T cells. Additionally, administration of ICOS-L, with or without IL-6 and/or IL-23, increased levels of granzyme B and CD107a in both CD4+ and CD8+ T cell populations following MUC1 vaccination, suggesting IL-17-polarization enhances T cell cytotoxicity. Studies are currently ongoing to evaluate the efficacy of IL-17-polarizing or conventional MUC1-targeting vaccination to protect MUC1-tolerant, transgenic mice against an orthotopic challenge of MUC1-expressing EO771 cells and findings will be presented at the AACR Annual Meeting. To the best of our knowledge, this study represents the first demonstration that IL-17-polarized immunity may be induced through vaccination, providing a novel platform for the generation of MUC1-specific immunity for the prevention of breast cancer. Citation Format: Amanda C. LaRue, Rebecca Carrell, Lindsay T. McDonald, Dayvia A. Russell, Stephen P. Ethier, Adam C. Soloff. Induction of IL-17-mediated cellular immunity targeting MUC1 through vaccination. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-092.